Research Interests

My research efforts integrate genetic, neurological, molecular and cellular means
to study the mechanisms underlying the pathogenesis of Alzheimers disease (AD). AD
is a progressive degenerative disease of the brain characterized clinically by gradual
loss of memory and cognitive function and, ultimately, death. The goal of my research
is to identify and characterize early molecular events contributing to the emergence
of cognitive decline and to discover information critical for the development of therapeutic
strategies for the treatment of this devastating disorder. Our most recent research
has been focusing on the following areas:

I: Novel role of PTEN in Neurodegeneration

The precise mechanisms underlying chronic neurodegeneration are largely unknown. Aberrant
cell cycle re-entry in mature neurons is frequently associated with degenerating neurons.
The cells cycle hypothesis states that aberrant cell cycle re-entry contributes to
the process of neurodegeneration. However, a direct proof of the causative role of
the associated dysregulated cell cycle events is lacking. Research in my laboratory
showed that PTEN, a key negative regulator of the PI-3K/Akt pathway and the best-known
tumor suppressor, is also important in control of neuronal cell cycle events. Loss
of PTEN is associated with degenerated neurons in AD brains. We are investigating
potential mechanisms which may impair PTEN function in neuronal cells during early
stage AD. Neuronal stress leads to post-translational modification of PTEN by a hitherto
little appreciated biochemical mechanism, S-nitrosylation, triggered by elevated nitric
oxide (NO).

We further showed that S-nitrosylation of PTEN can be functionally coupled to the
ubiquitination of PTEN and its accelerated degradation via the ubiquitin-proteasome
pathway. Since S-nitrosylated PTEN is detectable in early stage AD but not in normal
brain, we hypothesize that S-nitrosylation-induced PTEN degradation is at least partially
causative of AD progression. To test this hypothesis, we are currently undertaking
lentivirus-mediated gene therapy to deliver PTEN to affected neurons in an effort
to halt neurodegeneration in AD mouse models.

II: The Role of NO Signaling

The role of NO signaling in soluble oligomeric amyloid peptides-induced synaptic damage
in AD Genetic, molecular and cellular evidence strongly support a causal role of amyloid
β (Aβ) in AD pathogenesis. The concept of this amyloid hypothesis has been expanded
by the recent finding that the soluble oligomeric forms of Aβ rather than the highly
aggregated amyloid plaques selectively target synaptic activity. To better understand
the mechanisms underlying this Aβ-induced synaptic damage, we apply soluble oligomeric
Aβ to cultured neurons and rodent brains via intracerebral injection to establish
models to study the molecular and cellular consequences of Aβ toxicity on synaptic
activity, including synaptogenesis, long-term potentiation, gene expression and signaling
mechanisms. We currently focus on insulin and its downstream PI-3K/Akt signaling pathways
since impaired insulin signaling has recently been suggested to be the major factor
underlying the Aβ-induced synaptic damage. Specifically, we are investigating how
Aβ-induced changes in NO might affect S-nitrosylation of the protein components of
the insulin and PI-3K/Akt signaling pathways. We will investigate the NO signaling
events induced by synaptotoxic Aβand by neurotrophic insulin/BDNF, which are speculated
to be qualitatively distinct. In particular, we will address how these molecules/pathways
are differentially regulated by distinct NO signaling using various approaches including
NO imaging in live neuron.

Lastly, we also assess potential protective effect of a new class of Hsp90 inhibitors
in synaptic functions and investigate underlying mechanisms involving modulation on
NO signaling.